Wang Yi-Ting, Ashton Nicholas J, Therriault Joseph, Benedet Andréa L, Macedo Arthur C, Pola Ilaria, Aumont Etienne, Di Molfetta Guglielmo, Fernandez-Arias Jaime, Tan Kubra, Rahmouni Nesrine, Servaes Stijn Johannes G, Isaacson Richard, Chan Tevy, Hosseini Seyyed Ali, Tissot Cécile, Mathotaarachchi Sulantha, Stevenson Jenna, Lussier Firoza Z, Pascoal Tharick A, Gauthier Serge, Blennow Kaj, Zetterberg Henrik, Rosa-Neto Pedro
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Montreal, QC, Canada H4H 1R2.
Montreal Neurological Institute, Montreal, QC, Canada H3A 2B4.
Brain Commun. 2025 Jan 7;7(1):fcaf004. doi: 10.1093/braincomms/fcaf004. eCollection 2025.
Blood-based biomarkers have been revolutionizing the detection, diagnosis and screening of Alzheimer's disease. Specifically, phosphorylated-tau variants (p-tau, p-tau and p-tau) are promising biomarkers for identifying Alzheimer's disease pathology. Antibody-based assays such as single molecule arrays immunoassays are powerful tools to investigate pathological changes indicated by blood-based biomarkers and have been studied extensively in the Alzheimer's disease research field. A novel proteomic technology-NUcleic acid Linked Immuno-Sandwich Assay (NULISA)-was developed to improve the sensitivity of traditional proximity ligation assays and offer a comprehensive outlook for 120 protein biomarkers in neurodegenerative diseases. Due to the relative novelty of the NULISA technology in quantifying Alzheimer's disease biomarkers, validation through comparisons with more established methods is required. The main objective of the current study was to determine the capability of p-tau variants quantified using NULISA for identifying abnormal amyloid-β and tau pathology. We assessed 397 participants [mean (standard deviation) age, 64.8 (15.7) years; 244 females (61.5%) and 153 males (38.5%)] from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort where participants had plasma measurements of p-tau, p-tau and p-tau from NULISA and single molecule arrays immunoassays. Participants also underwent neuroimaging assessments, including structural MRI, amyloid-PET and tau-PET. Our findings suggest an excellent agreement between plasma p-tau variants quantified using NULISA and single molecule arrays immunoassays. Plasma p-tau measured with NULISA shows excellent discriminative accuracy for abnormal amyloid-PET (area under the receiver operating characteristic curve = 0.918, 95% confidence interval = 0.883 to 0.953, < 0.0001) and tau-PET (area under the receiver operating characteristic curve = 0.939; 95% confidence interval = 0.909 to 0.969, < 0.0001). It also presents the capability for differentiating tau-PET staging. Validation of the NULISA-measured plasma biomarkers adds to the current analytical methods for Alzheimer's disease diagnosis, screening and staging and could potentially expedite the development of a blood-based biomarker panel.
基于血液的生物标志物一直在彻底改变阿尔茨海默病的检测、诊断和筛查。具体而言，磷酸化tau变体（p-tau181、p-tau217和p-tau231）是识别阿尔茨海默病病理的有前景的生物标志物。基于抗体的检测方法，如单分子阵列免疫检测，是研究基于血液的生物标志物所指示的病理变化的有力工具，并且在阿尔茨海默病研究领域已经得到了广泛研究。一种新型蛋白质组学技术——核酸连接免疫夹心检测法（NULISA）——被开发出来，以提高传统邻近连接检测的灵敏度，并为神经退行性疾病中的120种蛋白质生物标志物提供全面的前景。由于NULISA技术在量化阿尔茨海默病生物标志物方面相对新颖，因此需要通过与更成熟的方法进行比较来进行验证。本研究的主要目的是确定使用NULISA量化的p-tau变体识别异常淀粉样β和tau病理的能力。我们评估了来自衰老与痴呆转化生物标志物（TRIAD）队列的397名参与者[平均（标准差）年龄，64.8（15.7）岁；244名女性（61.5%）和153名男性（38.5%）]，这些参与者通过NULISA和单分子阵列免疫检测对血浆中的p-tau181、p-tau217和p-tau231进行了测量。参与者还接受了神经影像学评估，包括结构磁共振成像、淀粉样蛋白正电子发射断层扫描和tau正电子发射断层扫描。我们的研究结果表明，使用NULISA量化的血浆p-tau变体与单分子阵列免疫检测之间具有极好的一致性。用NULISA测量的血浆p-tau181对异常淀粉样蛋白正电子发射断层扫描显示出极好的判别准确性（受试者工作特征曲线下面积=0.918，95%置信区间=0.883至0.953，P<0.0001）和tau正电子发射断层扫描（受试者工作特征曲线下面积=0.939；95%置信区间=0.909至0.969，P<0.0001）。它还具有区分tau正电子发射断层扫描分期的能力。对NULISA测量的血浆生物标志物的验证增加了目前用于阿尔茨海默病诊断、筛查和分期的分析方法，并可能加快基于血液的生物标志物组合的开发。
